Immunoglobulin A Nephropathy (IgAN) is a major cause of kidney disease worldwide and the leading cause of end stage renal disease (ESRD) among Asians. The affected individuals develop IgA1-containing antibody complexes that deposit in the kidney producing tissue injury. An increased serum level of galactose- deficient IgA1 (Gd-IgA1) has emerged as a useful biomarker of IgAN. Gd-IgA1 promotes formation and kidney deposition of IgA1-containing immune complexes, but the reason why IgAN patients have high Gd-IgA1 is not well understood. We have formed a multidisciplinary team of experienced investigators in order to accelerate the discovery of pathogenic mechanisms in IgAN. Through our collaborative efforts, we have already made significant contributions to the field, including the identification of the first Mendelian mutation that affects production of Gd-IgA1 and causes familial IgAN. We also completed a large genome-wide association study of IgAN involving 20,574 individuals and identified 15 common susceptibility alleles associated with disease risk. We observed that the worldwide distribution of common alleles closely parallels the disease epidemiology and that a burden of inherited risk alleles correlates with the age of disease onset. Our findings identify intestinal immunity as the key pathway involved in the disease pathogenesis. In this proposal, we hypothesize that both common and rare genetic variants contribute to the pathogenesis of IgAN and that these variants induce discrete lesions in innate and adaptive immunity, which inexorably lead to the development of kidney injury. We will leverage a large, well-characterized cohort of patients to define the biological and clinical impact of known risk variants and apply exome sequencing to define new genes underlying IgAN. The first part of this proposal will relate the newly discovered genetic factors to immunologic disease features, specific kidney biopsy findings, and clinical parameters of disease severity and progression. These studies are expected to refine the pathogenesis model and will be critical in enhancing the diagnosis and classification of IgAN. The second part of the proposal aims to define additional rare mutations with large effect underlying familial IgAN. Our innovative gene mapping strategy combines family screening for elevated serum Gd-IgA1 levels with exome sequencing to efficiently identify segregating pathogenic variants. We will perform functional analysis of candidate genes using knockdown and overexpression in IgA1-producing cell lines. Finally, we will aim to identify independent pathogenic mutations by sequencing of sporadic individuals with extreme values of Gd-IgA1 levels.